A research team led by scientists at the University at Buffalo (UB) says they have identified the biomarkers and pharmaceutical targets.
Published May 28 in Cell Reports, the research was led by Zhen Yan,
Ph.D., professor in the Department of Physiology and Biophysics in the
UB School of Medicine and Biomedical Sciences.
The paper focuses on the loss of a gene called Shank3, an important risk factor for autism spectrum disorders (ASD). The researchers trace how this risk factor disrupts communication between neurons,
leading to social deficits in mice. And, in their most important
finding, they are able to reverse these neuronal disruptions, restoring
normal behavior in mice.
Previous studies have shown that approximately 84% of people with a
Shank3 deletion or loss-of-function mutation had an ASD. But just how
this occurs has remained unknown.
The Cell Reports study notes that mice with a Shank3 deficiency
exhibited "drastically reduced" interest in social stimuli, i.e., other
mice, versus inanimate objects, suggesting "severe social deficits."
They also spent significantly more time in repetitive self-grooming than
The researchers also found that the Shank3 deficiency plays a key role
in how neurons communicate.
It has a significant effect on the
activation of the NMDA (n-methyl-D-aspartate) receptor, which is
critical to learning and memory.
Zhen Yan, Ph.D., professor in the department of physiology and
biophysics in the UB School of Medicine and Biomedical Sciences,
explained that the Shank3 deficiency disrupts the trafficking of this
receptor and its function at critical transmission sites in the brain.
That disruption, they found, results from the dysregulation of actin
filaments, which act as a kind of cellular "highway" in the brain's
prefrontal cortex, the command center for "high-level" executive
functions and a key region implicated in ASD.
"This research is the first to show that, in animals, abnormal actin
regulation causes autism-like behaviors," said Dr. Yan. "Actin filaments
are very dynamic structures that are constantly being assembled and
disassembled, processes controlled by numerous regulators.”
When something upsets the equilibrium of actin filament assembly, key cellular functions fall apart.
"With Shank3 deficiency, we have found that the expression or activity
of some actin regulators, such as cofilin, is altered," continued Dr.
Yan. "This upsets the equilibrium of actin filament assembly, which, in
turn, disrupts the normal delivery and maintenance of NMDA and other
The result is a significant effect on the functional plasticity of the
synapse, which, in turn, leads to the manifestation of some autistic
behaviors. In its most dramatic finding, the researchers found they were
able to reverse this process, restoring normal behaviors in the
Shank3-deficient mice, once the activity of cofilin or other regulators
was returned to normal. This, in turn, restored actin dynamics at
cortical synapses, allowing for the normal trafficking and functioning
of NMDA receptors.
"Once actin filaments and NMDA receptors returned to normal, we
observed a robust and long-lasting rescue of the social interaction
deficits and repetitive behavior in the Shank3-deficient mice," said Dr.
Yan. "Our results suggest a promising therapeutic strategy for treating
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